Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

• MeSH
• B-lymfocyty imunologie   metabolismus   MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• maturační antigen B-buněk * genetika   MeSH
• mendelovská randomizace MeSH
• mnohočetný myelom * genetika   MeSH
• receptor TACI genetika   MeSH
• studie případů a kontrol MeSH
• telomery genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• maturační antigen B-buněk * MeSH
• receptor TACI MeSH
• TNFRSF13B protein, human MeSH Prohlížeč

During innate immune responses, myeloid differentiation primary response 88 (MyD88) functions as a critical signaling adaptor protein integrating stimuli from toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family and translates them into specific cellular outcomes. In B cells, somatic mutations in MyD88 trigger oncogenic NF-κB signaling independent of receptor stimulation, which leads to the development of B-cell malignancies. However, the exact molecular mechanisms and downstream signaling targets remain unresolved. We established an inducible system to introduce MyD88 to lymphoma cell lines and performed transcriptomic analysis (RNA-seq) to identify genes differentially expressed by MyD88 bearing the L265P oncogenic mutation. We show that MyD88L265P activates NF-κB signaling and upregulates genes that might contribute to lymphomagenesis, including CD44, LGALS3 (coding Galectin-3), NFKBIZ (coding IkBƺ), and BATF. Moreover, we demonstrate that CD44 can serve as a marker of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and that CD44 expression is correlated with overall survival in DLBCL patients. Our results shed new light on the downstream outcomes of MyD88L265P oncogenic signaling that might be involved in cellular transformation and provide novel therapeutical targets.

• Klíčová slova
• CD44, DLBCL, Galectin-3, LGALS3, MYD88, NF-kB, lymphoma, oncogenic signaling,
• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• antigeny CD44 genetika   metabolismus   MeSH
• difúzní velkobuněčný B-lymfom * patologie   MeSH
• galektin 3 metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• myeloidní diferenciační faktor 88 genetika   metabolismus   MeSH
• NF-kappa B * genetika   metabolismus   MeSH
• stanovení celkové genové exprese MeSH
• transkripční faktory bZIP genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• antigeny CD44 MeSH
• BATF protein, human MeSH Prohlížeč
• CD44 protein, human MeSH Prohlížeč
• galektin 3 MeSH
• myeloidní diferenciační faktor 88 MeSH
• NF-kappa B * MeSH
• NFKBIZ protein, human MeSH Prohlížeč
• transkripční faktory bZIP MeSH

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.

• MeSH
• adaptorové proteiny signální transdukční genetika   imunologie   MeSH
• B-lymfocyty imunologie   patologie   MeSH
• chromatin chemie   imunologie   MeSH
• chromozomální proteiny, nehistonové genetika   imunologie   MeSH
• genetická predispozice k nemoci * MeSH
• hodnocení rizik MeSH
• intergenová DNA genetika   imunologie   MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• mnohočetný myelom farmakoterapie   genetika   imunologie   patologie   MeSH
• nádorové proteiny genetika   imunologie   MeSH
• plazmatické buňky imunologie   patologie   MeSH
• polymorfismus genetický MeSH
• primární buněčná kultura MeSH
• proteiny buněčného cyklu genetika   imunologie   MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• regulace genové exprese u nádorů MeSH
• represorové proteiny genetika   imunologie   MeSH
• sekvence nukleotidů MeSH
• transkripční elongační faktory genetika   imunologie   MeSH
• typy dědičnosti MeSH
• výměnné faktory guaninnukleotidů genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• CDCA7L protein, human MeSH Prohlížeč
• CEP120 protein, human MeSH Prohlížeč
• chromatin MeSH
• chromozomální proteiny, nehistonové MeSH
• ELL2 protein, human MeSH Prohlížeč
• intergenová DNA MeSH
• nádorové proteiny MeSH
• PREX1 protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• represorové proteiny MeSH
• SMARCD3 protein, human MeSH Prohlížeč
• transkripční elongační faktory MeSH
• výměnné faktory guaninnukleotidů MeSH
• WAC protein, human MeSH Prohlížeč

Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapies. Areas of unmet need include the management of patients with high-risk MM, those with reduced performance status and those refractory to standard therapies. Ongoing research into the biology and early detection of MM as well as the development of novel therapies, such as immunotherapies, has the potential to influence MM practice in the future.

• Klíčová slova
• clinical presentation, plasma cell disease, risks factors, survival, treatment,
• MeSH
• cyklin D1 genetika   MeSH
• exozom genetika   MeSH
• genetická predispozice k nemoci MeSH
• histondemethylasy genetika   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• míra přežití MeSH
• mnohočetný myelom diagnóza   epidemiologie   genetika   terapie   MeSH
• mutace MeSH
• nádorové biomarkery genetika   MeSH
• plazmatické buňky imunologie   patologie   MeSH
• represorové proteiny genetika   MeSH
• rizikové faktory MeSH
• transkripční elongační faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• CCND1 protein, human MeSH Prohlížeč
• CDCA7L protein, human MeSH Prohlížeč
• cyklin D1 MeSH
• DIS3 protein, human MeSH Prohlížeč
• ELL2 protein, human MeSH Prohlížeč
• exozom MeSH
• histondemethylasy MeSH
• KDM1A protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• represorové proteiny MeSH
• transkripční elongační faktory MeSH

Multiple myeloma (MM) is the second most common blood malignancy. Epidemiological family studies going back to the 1920s have provided evidence for familial aggregation, suggesting a subset of cases have an inherited genetic background. Recently, studies aimed at explaining this phenomenon have begun to provide direct evidence for genetic predisposition to MM. Genome-wide association studies have identified common risk alleles at 24 independent loci. Sequencing studies of familial cases and kindreds have begun to identify promising candidate genes where variants with strong effects on MM risk might reside. Finally, functional studies are starting to give insight into how identified risk alleles promote the development of MM. Here, we review recent findings in MM predisposition field, and highlight open questions and future directions.

• MeSH
• alely MeSH
• celogenomová asociační studie MeSH
• genetická predispozice k nemoci * MeSH
• genetická variace MeSH
• genom lidský MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• mnohočetný myelom epidemiologie   genetika   MeSH
• riziko MeSH
• sekvenční analýza DNA MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH